Description

Perioperative blood loss and allogeneic blood transfusion are major complications of cardiac surgery, which increase perioperative complications, perioperative mortality and medical costs. This study addresses the unmet need for optimizing coagulation management in cardiac surgery by comparing the efficacy and safety of 4-factor prothrombin complex concentrates (PCC) and fresh frozen plasma (FFP). he trial is designed as a non-inferiority, randomized controlled study to assess whether PCC is non-inferior to FFP in reducing perioperative blood loss and transfusion needs in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Patients who signed informed consent, aged 18 to 80 years, receiving elective CABG or valve replacement or valvuloplasty under CPB will be included. 816 subjects will be randomly divided into 2 groups (PCC group and FFP group), with 408 cases in each group. Preoperative management, anesthetic and surgical techniques will be standardized for both groups. When activated partial thromboplastin time (APTT) is prolonged (> 45 s), patients will be given 8~15 IU/kg PCC or 6~10 ml/kg FFP according to the allocation. All the patients will be followed up respectively at 24 hours, 48 hours, 72 hours and 7 days after the surgery to record observations relevant to the study and the results of laboratory testing. The laboratory tests include hemoglobin concentration, hematocrit, platelet count, INR, PT, APTT, fibrinogen levels and blood biochemistry parameters. The primary outcome is the volume of blood loss within 24 hours after surgery. The secondary outcomes include (1) the total units of allogeneic red blood cells (RBCs) transfused within 7 days after surgery and (2) hemostatic response (effective if no hemostatic interventions occurred from 60 minutes to 24 hours after treatment initiation). Adverse events and serious adverse events will be monitored as safety outcomes.

Modified intent-to-treat analysis will be used for all valid variables. All randomised subjects in the study, regardless of adherence to the study process or whether an adverse event occurs before or after the intervention, should be included in the analysis. Sensitivity analysis will be performed to assess potential bias from protocol deviations or missing data. Baseline characteristics will be tabulated and compared between the PCC and FFP groups using absolute standardised differences, and the threshold will be calculated using the formula (1.96×√[n1+n2]/[n1×n2]). A value exceeding this threshold will be considered imbalanced between groups. Unbalanced baseline factors and different study centers will be further adjusted by multivariable regression models.

The primary outcome, the volume of blood loss within 24 hours after surgery, will be compared using one-tailed ttest. If there exists unbalanced baseline characteristics, the treatment effect (difference in means between the PCC and FFP groups) will be estimated using a linear regression model adjusted for centers and any imbalanced baseline covariates. The non-inferiority test will be conducted using the estimated difference minus the non-inferiority margin (200 mL) in the numerator, and the estimated standard error of the difference in the denominator. Non-inferiority will be concluded if the upper bound of the 99.7% confidence interval was below the predefined non-inferiority margin of 200 mL, corresponding to a one-sided P value < 0.025. For the continuous secondary outcome, the total units of allogeneic RBCs transfused during and within 7 days after surgery will be compared using a t-test with log transformation of the variable. The rate of hemostatic response will be compared using the chi-square test. Treatment effects will be reported as risk ratios and mean differences for binary and continuous outcomes respectively with 95% confidence intervals. If there exists unbalanced baseline characteristics, the secondary outcomes will be regressed against the group allocation, centers and the unbalanced factors using linear regression or Poisson regression models. The following subgroups will be analysed: age (<65 years/ ≥65 years), gender (male/female), study center, NYHA class (I and II/III and IV), surgery type (simple/complex surgery) and CPB duration (≤120 minutes, 121-180 minutes, >180 minutes). For safety outcomes, we will only describe the incidence of overall adverse events, SAEs, and component adverse events without statistical tests between two groups. A two-sided P-value < 0.05 was considered indicative of statistical significance.

Our independent Data Safety Monitoring Board (DSMB), which includes an epidemiologist, a pharmacologist, an anesthesiologist, and a blood transfusion specialist, conducted an interim review of our study. Considering the shortage of blood resources and the difficulties in large-sample recruitment, the DSMB recommended adding an interim analysis. Therefore, an interim analysis was planned after 50% of the target enrollment had been achieved. o ensure statistical rigor, the Lan-DeMets alpha-spending approach with O'Brien-Fleming boundaries was implemented for interim efficacy and futility evaluation, offering conservative thresholds early in the trial. With the same standard deviation (824.38 mL) and the superior margin (200 mL) is, as well as the 90% power and 10% dropout rate, we recalculated the sample size and found out that 816 patients in total should be recruited. Thus our interim analysis will be conducted when 408 patients recruited.